Axonal damage is cause of major clinical disability in a wide range of neurological disorders, including multiple sclerosis (MS). Although considerable progress has been made in the detection of the early signs of axonal damage, still very little is known about the potential causative factors and the related signaling events. Thus, therapeutic approaches aimed at preventing or repairing damaged axons are not yet available. Our laboratory has recently reported the involvement of cytoplasmic HDAC1 in the impairment of mitochondrial transport and the onset of axonal swellings. This experimental plan proposes to characterize this novel intracellular signaling mechanism and use in vitro and in vivo models to characterize the role of specific isoforms of histone deacetylases in axonal damage in demyelinating disorders. PUBLIC HEALTH RELEVANCE: Axonal damage is cause of major clinical disability in a wide range of neurological disorders, including multiple sclerosis. Although considerable progress has been made in the detection of axonal damage in demyelinating disorders still very little is known about the underlying signaling events and this is the major focus of this grant. The results of the proposed experimental plan are expected to enhance our current state of knowledge on axonal damage and lead to the identification of potential novel therapeutic targets for multiple sclerosis and other disorders characterized by axonopathy.